Organ-based dosimetry of a novel albumin-binding 177Lu-PSMA agent: interim results of phase 1 clinical trial of Ludotadipep

Introduction: Ludotadipep is a novel prostate specific membrane antigen (PSMA) targeting therapeutic agent radiolabeled with ¹⁷⁷Lu, which has an albumin binding motif. To determine the optimal dose and number of cycles for treatment of metastatic castration resistant prostate cancer, assessment of absorbed dose of critical organs were necessary.

Methods: In phase 1 clinical trial with dose-escalation design of Ludotadipep, 6 subjects were enrolled for each of the following doses: 1850±190 2775±280, 3700±370, and 4625±460 MBq. In this dose-escalation design, subjects were monitored for safety for 8 weeks before the next dose was administered. Whole body scan (WBS) and abdominal SPECT/CT were acquired at 2, 24, 48, 72, and 168 hours after administration of Ludotadipep. A vial of 3.7 MBq was used as a reference source to estimate the calibration factors of WBS and SPECT/CT. Radioactivity of liver, kidneys, and spleen at each time point were measured on SPECT/CT with attenuation and scatter correction. Radioactivty of salivary glands and lungs were estimated from the WBS with attenuation and scatter correction according to MIRD pamphlet No. 16. Red marrow radioactivity was calculated from blood samples obtained at 3, 10, 30, 60 and180 minutes, and 24, 48 and 72 hours after injection of Ludotadipep from 6 subjects. Organ and tumor segmentation, time-radioactivity curve fitting, and organ-based absorbed dose calculation was performed using IDAC-Dose 2.1 (QDOSE v1.1.18, ABX-CRO advanced pharmaceutical services, Dresden, Germany). Tumor absorbed dose was calculated for 19 tumor lesions via sphere model also by the QDOSE software.

Results: Radiation absorbed dose given to the source organs were 1.24±0.70 Gy/GBq for salivary glands, 0.77±0.28 Gy/GBq for kidneys, 0.14±0.06 Gy/GBq for liver, 0.050±0.02 Gy/GBq for lungs, and 0.039±0.01 Gy/GBq for red marrow. Radiation absorbed dose to tumors (11.1±8.0 Gy/GBq) was significantly higher than that to the source organs. Considering critical threshold of absorbed dose of kidneys as 23 Gy and red marrow as 2 Gy, kidney is the critical organ of Ludotadipep treatment.

Conclusions: Ludotadipep is a safe radiotherapeutic agent targeting PSMA with kidney being the critical organ. High efficacy is expected based on the high tumor absorbed dose, which is probably associated with the long circulation time induced by the albumin-binding property.